In patients with type 2 diabetes at high cardiovascular (CV) risk, oral semaglutide demonstrated non-inferior cardiovascular safety to placebo, showing no significant increase in major adverse cardiovascular events (MACE), which included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
PICO Summary
Population:
Adults (N=3183) with type 2 diabetes, aged ≥50 with established CV disease or moderate chronic kidney disease, or aged ≥60 with additional CV risk factors.
Intervention:
Oral semaglutide, dose-escalated to a maintenance dose of 14 mg daily following an initial titration (3 mg for 4 weeks, then 7 mg for 4 weeks).
Comparison:
Placebo added to standard of care, including glucose-lowering agents (with the exception of other GLP-1 receptor agonists).
Outcome:
- Efficacy: The primary outcome was time to first MACE, defined as CV death, non-fatal myocardial infarction, or non-fatal stroke. Semaglutide achieved non-inferiority for MACE compared to placebo with a hazard ratio upper limit below 1.8.
- Safety and Tolerability: Oral semaglutide was generally well-tolerated; however, gastrointestinal side effects, such as nausea, vomiting, and diarrhoea, were frequent, particularly during dose escalation.
Clinical Summary
Main Finding:
Oral semaglutide was non-inferior to placebo for the primary endpoint of time to first MACE, indicating that it does not increase CV risk in high-risk type 2 diabetes patients. Specifically, the study observed a hazard ratio of 0.79 (95% CI 0.57–1.11), demonstrating non-inferiority as per regulatory standards. In absolute terms, MACE events were reported in 61 patients (3.8%) receiving semaglutide compared to 76 (4.8%) in the placebo group over a median follow-up of 16 months.
Clinical Relevance:
These findings underscore oral semaglutide’s role as a safe CV option for high-risk patients, particularly for those who prefer oral medication over injectable options. The treatment effect on MACE was generally consistent across subgroups defined by age, sex, and baseline CV history, supporting broader applicability. Importantly, oral semaglutide’s convenience as a daily tablet might improve adherence among patients averse to injectables, aligning with the study’s implication that oral GLP-1 receptor agonist therapy could fill a significant therapeutic gap.
Study Overview:
- Type of Study: Randomised, double-blind, placebo-controlled, international CV outcomes trial (PIONEER 6).
- Sample Size & Population: 3183 patients, mostly aged ≥50 years with established CV disease or moderate chronic kidney disease or aged ≥60 with at least one CV risk factor.
- Intervention Duration & Doses: Dose-escalation to 14 mg daily over an 8-week period, then administered for the duration of the trial.
- Comparison: Placebo.
Outcomes:
- Primary Measure (MACE): Achieved non-inferiority for the composite endpoint of MACE, with oral semaglutide showing a hazard ratio of 0.79 (95% CI, 0.57–1.11).
- Secondary Measures: Other CV outcomes, including the risk of CV death, were not significantly different, further supporting safety.
- Safety Profile: Higher incidence of gastrointestinal adverse events in semaglutide users (nausea, vomiting, diarrhoea), especially during initial titration, which often resolved with time or dose adjustment.
Considerations:
The shorter duration and event-driven nature of the study (compared to other CV outcome trials with GLP-1 receptor agonists) limit insights on long-term safety. Future studies might be necessary to confirm these findings over extended use.
Reference:
Bain, S. C., Mosenzon, O., Arechavaleta, R., et al. (2018). Diabetes Obesity Metabolism, 21(3), 499–508. doi:10.1111/dom.13553
Disclosure:
This article on Hormone Insight was created with both human and AI assistance. The human expert editor reviewed the article before publication to ensure accuracy, quality, and clarity.
